The injection of many antibiotics produces irritation and, potentially, illegal drug residues at the injection site of food-producing animals. Current cattle practice is oriented toward changing from an intramuscular injection of drugs and vaccines, which then leaves both irritation and possibly drug residues in edible meat, to subcutaneous injection, which places those unwanted occurrences at the surface of the carcass in cattle. Because the hide of cattle is removed at slaughter, the injection sites are potentially visible and will be trimmed from the carcass. Even if that is not done, the edible meat is not damaged because the injection is not into muscle. Nevertheless, even with subcutaneous administration, injection site irritation and potentially violative drug residues still remain on an edible portion of the carcass, namely the surface of the carcass itself.
Furthermore, any violative drug residues at the injection site cannot be monitored by current United States Department of Agriculture (USDA) inspectors, who require a "target tissue" for residue monitoring to homogeneously contain drug residues and always be readily identifiable to the layman. These target tissues are now defined as the kidney, liver, muscle and fat; and an injection site in any edible tissue, regardless of whether the injection is intramuscular or subcutaneous, fails the criteria for a target tissue because it is not always readily identifiable, circumscript or homogenous with respect to drug residues.
The only alternative for antibiotics which have injection site residues, that are unacceptable as target tissues, is to use surrogate target tissue with which to monitor residue depletion. In that case, the surrogate target tissue is not the tissue in which potentially unsafe residues reside, but rather is the circumscript and/or homogeneous tissue (with respect to incurred drug residues) for which residues can be monitored until the time after drug administration at which all other drug residues in tissues decrease to safe levels. Because it is a surrogate target tissue, residues must decrease to a much lower concentration than those determined to be safe for that tissue from toxicological studies and food consumption values, in essence, penalizing that tissue's safe concentration because it is being used as a surrogate for the injection site.
Ceftiofur crystalline free acid sterile oil suspension (CCFA-SS), which will be described further below, is a sustained-release ceftiofur product under development that provides for prolonged absorption from the injection site and thus affords a single injection treatment of bacterial diseases in animals. The prolonged absorption of the drug from the injection site makes the injection site contain the highest concentration of drug residues for the longest period of time (several weeks) during which time the concentration in all other tissues decreases to non-detectable levels. This makes the use of a surrogate target tissue impossible for this antibiotic.
This is not unique to ceftiofur crystalline free acid, but rather is common to all sustained-release injectable compounds. Heretofore, the only alternative has been to utilize the surrogate tissue approach described above, as a result of injection site residues remaining with the edible carcass of food-producing animals.
Therefore, what is needed in the art is a way to administer to food-producing animals therapeutic agents, and specifically, antibacterial agents such as ceftiofur crystalline free acid, which satisfies the applicable regulatory and consumer health requirements regarding human food safety. In accordance with the present invention, this may be achieved by removing prolonged drug residues from the edible tissues of the food-producing animal, and yet provide the food-animal producer with products that offer the convenience of sustained-delivery injectable systems, that have slaughter withdrawal periods that optimize the return on their investment and that have use flexibility in the field situation.
International Publication No. WO 94/20505, published Sept. 15, 1994, discloses ceftiofur crystalline free acid, its preparation and its method of administration. In the examples in that publication, it states that cattle were administered ceftiofur crystalline free acid by injection intramuscularly or subcutaneously either in or on the edible tissues of the animals. At page 10 of the publication it refers to antibiotics implants disclosed in U.S. Pat. No. 5,079,007 and to various pharmaceutical dosage forms exemplified in U.S. Pat. No. 4,902,683.
Putnam, Controlled Release of Antibiotic Salts from an Implant, U.S. Pat. No. 5,079,007, Jan. 7, 1992, discloses a formulation, in pellet or tablet form, providing for the controlled release implant of a cephalosporin antibiotic, particularly ceftiofur, consisting of: (a) a crystalline salt of the cephalosporin, particularly ceftiofur hydrochloride; (b) an amorphous salt of the cephalosporin, particularly ceftiofur sodium; and (c) excipients. It only discloses intramuscular implantation as the preferred route of administration.
Amin et al., Crystalline Cephalosporin Hydrohalide Salts, U.S. Pat. No. 4,902,683, Feb. 20, 1990, discloses the crystalline hydrochloride and hydrobromide salts of the cephalosporin antibiotic, ceftiofur. It discloses a variety of dosage forms, such as oral (e.g., capsules, tablets), topical, rectal (e.g., suppositories) and injectable preparations, as well as a variety of routes of administration, such as oral, intramuscular and intravenous. In fact, the product, EXCENEL.RTM. Sterile Suspension (having ceftiofur hydrochloride as its active ingredient), is currently marketed in the U.S. as a ready-to-use oil suspension product for the treatment/control of swine bacterial respiratory disease and is administered by intramuscular injection. These intramuscular injections are administered exclusively in edible tissues of the food-producing animals, namely the neck (often using the base of the ear as a landmark but not using the ear specifically as a site of injection), hindleg, and flank of the animal.
Labeeuw et al., Cephalosporin Derivatives, Process for Preparation Thereof and Drugs Containing Said Derivatives Usable as Antibiotics, U.S. Pat. No. 4,464,367, Aug. 7, 1984, discloses the cephalosporin antibiotic, ceftiofur, as well as alkali, alkaline earth and amine salts thereof. In fact, the product, NAXCEL/EXCENEL.RTM. Sterile Powder (having ceftiofur sodium as its active ingredient) is also currently marketed throughout the world for the treatment/control of bovine and swine bacterial respiratory diseases. This product must be reconstituted with sterile water before it is injected intramuscularly into cattle or swine. Once again, these injections are made into edible tissues including the neck, foreleg or hindleg, and flank of the animal.
It is known in the art to use ear tags for identification and/or for pest control in animals, such as cattle. For example: U.S. Pat. No. 4,506,630 discloses an ear tag attached to which is a vial containing, for example, a pesticide or insect repellant. U.S. Pat. No. 4,631,231 discloses pyrethroid-containing mouldings, preferably ear tags, for combating ectoparasites, e.g., flies, mites or ticks, on animals, especially cattle. U.S. Pat. No. 4,495,898 discloses a pest control device for animals composed of an identification tag to be attached to the animal, especially the ear, and a reservoir of insecticide.
Several solid hormonal implants (i.e., implantable pellets) for increased weight gain and feed efficiency are marketed, with the approval of the Food and Drug Administration (FDA) --Center for Veterinary Medicine (CVM), as over-the-counter products, not requiring the order of or the supervision of a veterinarian, such as the following: IMPLUS-H.RTM. Heifer Implants and IMPLUS-S.RTM. Steer Implants (Ivy Labs); SYNOVEX.RTM.C Calf Implants, SYNOVEX.RTM.H Heifer Implants and SYNOVEX.RTM.S Steer Implants (Syntex); COMPUDOSE.RTM. 200 Estradiol (Elanco); RALGRO.RTM. Beef Cattle Implants and RALGRO.RTM. Feedlot Lamb Implants (Malinkrodt); REVALOR.RTM.-S For Feedlot Steers, FINAPLIX.RTM.-H For Feedlot Heifers and FINAPLIX.RTM.-S For Feedlot Steers (Hoechst Roussel). The ear is a common place for administration of approved OTC implants. For example, French Pat. No. FR2239988 discloses animal hormone implants for use especially behind the ear. U.S. Pat. No. 3,428,729 discloses a controlled release medicament, such as a hormone, especially for subcutaneous ear implants in animals.
Japanese Pat. No. J59181208 published Oct. 15, 1984 discloses a pharmaceutical-containing adhesive formulation for external application having a pharmaceutical in an adhesive base and used, for example, to apply to the auricle (i.e., the earlobe) of the ear. These transdermal devices, which are bent to attach to both sides of the earlobe, are adhered to the stratum corneum of the ear (i.e., the surface of the ear), a location chosen most likely to maximize adhesion and minimize removal of the device by the animal.
"Microchip Implant Sites Identified by USDA," Feedstuffs, Sept. 30, 1996, page 6, reports that the Food & Drug Administration has given clearance for the implanting of microchips in food animals, clearing the way for the Destron Fearing Corp. to market its electronic identification (EID) products to the livestock industry. The four implantation sites that were identified in an animal, all sites being inedible tissue, were as follows: (1) subcutaneous on the scutiform cartilage at the base of the ear; (2) subcutaneous above the dewclaw of the foot; (3) subcutaneous in the infraorbital fossa in swine; and (4) in the ligamentum nuchae in horses.
T. G. Watson, B. C. Hosking and F. G. Hooke, "Efficacy of Doramectin Against Experimental Infections by Some Nematode Parasites in Cattle in New Zealand," New Zealand Veterinary Journal, vol. 43, no. 2, pages 67-69 (1995), studied the efficacy of the novel avermectin, doramectin, against experimental larval and adult infections of three species of nematode parasites important to cattle production in New Zealand. Given as a single subcutaneous injection behind the ear (as a landmark), doramectin was very effective against the parasite when compared to infections established in untreated controls. In M. McHardy and D. W. T. Morgan, "Treatment of Theileria annulata Infection in Calves with Paraquone," Research in Veterinary Science, vol. 39, no. 1, pages 1-4 (1985), calves were infected with this parasite by subcutaneous injection in front of the right ear (once again, as a landmark). Particular groups of the calves were treated by intramuscular injection on the right side of the neck with parvaquone, resulting in certain animals being clinically cured.
P. Houpert et al., "Intra- vs Intermuscular Injections in Swine," Veterinary Research, vol. 24, no. 3, pages 278-285 (1993), determined the exact localization (intra- or intermuscular) of a drug administered by a so-called intramuscular technique. It concluded that an injection in the neck (perpendicular to the skin surface using the landmark of just behind the base of the ear) was the most appropriate site for intramuscular injection in pigs. F. B. Bilalov, "Haematological and Immunomorphological Investigation of Pigs Given Swine Erysipelas Vaccine as a Single Intramuscular Deposit or by Tissue Infiltration," Diagnosis of Infectious Diseases of Farm Animals," (Russian) pages 132-135 (1982), ten pigs were given a single intramuscular injection of 1 ml of the VR2 (BP2) attenuated strain of Erysipelothris rhusiopathiae, in the conventional way, into the neck 10 cm from the ear. I. Rumachik, I. Soloneko and P. E. Sakhonchik, "Effectiveness of Tuberculin Testing in Pigs at Various Sites on the Body," Veterinarnaya Nauka--Proizvodstvu (Russian), vol. 26, pages 36-44 (1988), found that intradermal injection of a small volume (approximately 0.1 to 0.5 mL) of the tuberculin antigen in the skin of the ear flaps of pigs gave more reliable results than injection into the neck or lumbar region. I. Genov, V. Tsutsumanski and K. H. Lalov, "Trial to Obtain and Use Allergen in Animal Leukosis Diagnostics," Vet. Med. Nauki, Vol. 17(2) pages 42-47 (1980, Recd. 1981), found that the most suitable site to inject the allergen proved to be the tail fold for cattle and sheep and the dorsal part of the ear near the medial line for pigs. The allergen reaction may be used for quick herd diagnosis of leukosis. Once again, this is a nontherapeutic diagnostic test using a small volume (approximately 0.1 to 0.5 mL) of an antigen injected intradermally, at the base of the ear of swine, to allow visualization of the local tissue reaction (similar to tuberculin testing in humans). P. D. McKercher and H. L. Bachrach, "A Foot-and-Mouth Disease Vaccine for Swine," Can. J. Comp. Med., vol. 40(1), pages 67-74 (1976), found that significant protection against this disease was afforded when small volumes (0.1 to 0.5 mL) of disease-preventing vaccine were applied with a jet injector gun to the ear (intradermally and intramuscularly in the dorsal part of the ear) or neck of swine. In other experiments, the vaccine was administered prophylactically subcutaneously by hypodermic syringe to the dorsal part of the ear, and was administered subcutaneously by injection gun to the posterior side of the ear to check for tissue reactions. The latter is a biological agent (i.e., vaccine) administered in small volume rather than a pharmaceutical agent administered in relatively large volume (1 to 15 mL) as in the present invention. Th. Alogninouwa et al., "Comparative Efficacy of Ivermectin and Deltamethrin in the Treatment of Porcine Scabies," Revue de Medecine Veterinaire, vol. 144, no. 7, pages 599-605 (1993), discusses the efficacy of ivermectin in comparison to another antiparasitic in swine. Ivermectin was administered by subcutaneous injection at the base of the ear, not in the ear. In this method of administration, the ear is used as a landmark and the injection is made in the pig's neck just caudal to (i.e., behind) the base of the ear, within a couple of centimeters. The injection site remains on the carcass when the ears are removed. In the present invention, where the drug is administered subcutaneously in the posterior side of the auricle of the ear, the injection site remains with the ear upon its removal at the slaughterhouse.
M. A. Koutchoukali et al., "Primary Vaccination Against Rabies in the Dog by the Intradermal Route: Comparison of its Effectiveness Depending on the Site of the Injection: Ear or Thigh," Revue de Medecine Veterinarie, vol. 136, no. 7, pages 505-508 (1985); B. Toma et al., "Vaccination in the Dog Against Rabies: Serological Response Compared One Year After Vaccination by the Intradermal or Subcutaneous Route," Recueil de Medecine Veterinaire, vol. 159, no. 7, pages 645-652 (1983); describe vaccination of dogs for rabies by intradermal injection in the internal surface of the ear, in comparison to subcutaneous administration in the lateral flank and to the rear leg. These references focused on intradermal versus subcutaneous administration with secondary emphasis on the location of administration. Intradermal administration in the ear of the vaccines worked better than the other methods of administration with regard to maintenance of titers.
R. F. Borgman et al., "Ear Lesions Produced in Rabbits by Sterol Injections," American Journal of Veterinary Research, vol. 33, no. 11, pages 2309-2315 (1972), studied ear lesions induced in rabbits as a model for atherosclerosis. Lesions were produced when cholesterol, cholesterol esters and similar compounds were intradermally injected into the auricles (i.e., flaps) of rabbit ears.
As demonstrated by the above references, the administration by injection of an antimicrobial sterile suspension formulation (e.g., ceftiofur crystalline free acid sterile suspension) subcutaneously (SC) in the neck, flank, or other subcutaneous sites on the carcass for the treatment of bacterial diseases, such as bovine respiratory disease (BRD) and swine respiratory disease (SRD) is known. The subcutaneous aural (i.e., ear) administration of hormones as solid dose implants is known. Implants of antibiotics are known but are typically administered intramuscularly in the edible tissues of the food-producing animal, not in the ear. Small-volume vaccines have been administered successfully intradermally in the ear of dogs and swine. Also in swine, diagnostic allergens and a vaccine in small volumes have been administered subcutaneously in the dorsal part or the posterior side of the ear.
However, the aural administration of an antibiotic injected subcutaneously in the posterior side of the auricle of the ear of cattle or swine is novel. More specifically, the aural administration of an antimicrobial sterile suspension injected subcutaneously in the posterior ear is novel. Certainly, none of these references disclose the ear as the preferred route of administration for a pharmaceutical compound, and specifically an antimicrobial agent. No antimicrobial, or, more specifically, no variable dose formulation of an antimicrobial, is disclosed as being administrated in the ear.
Furthermore, the administration in the ear, according to the present invention, resulted in unexpected results in the properties/performance of the antimicrobial suspension. As will be described further below, it was observed that the subcutaneous aural administration of an antimicrobial sterile suspension provided comparable systemic plasma concentrations of active drug, and slightly faster absorption, relative to subcutaneous administration in the neck.